Methods for influencing blood pressure, both to lower and to raise it, are extremely important because many serious diseases and conditions involve aberrations in blood pressure.
Hypertension is a major public health problem due to its high prevalence and increased risk of cardiovascular morbidity and mortality (Yildirir et al. Europace 4:175-182, 2002; Mulvany, News Physiol. Sci. 17:105-109, 2002). Systemic hypertension is the most prevalent cardiovascular disorder in the United States, affecting over 60 million Americans. In spite of increasing public awareness and a rapidly expanding array of antihypertensive medications, hypertension remains one of the leading causes of cardiovascular morbidity and mortality. Hypertension treatments have focused on stimulating the relaxation of the peripheral vasculature (vasodilation), depressing cardiac function, or by stimulating salt transport by blocking epithelial transport of sodium or chloride (diuresis) (“Textbook of Medical Physiology”, Guyton and Hall, eds. p. 234, 1996, W. B. Saunders). In addition, adverse metabolic effects have been observed with treatment using certain classes of antihypertensive treatment in coronary disease prevention (“Cecil Textbook of Medicine” pp. 252-269 (1992) W. B. Saunders).
At the other end of the spectrum, shock is a condition in which blood perfusion of peripheral tissues is inadequate to sustain normal tissue metabolism. The fundamental defect in this condition is usually hypotension, so that oxygen delivery or uptake is inadequate for aerobic metabolism. This defect results in a shift to anaerobic metabolism, with increased production and accumulation of lactic acid. When shock persists, impaired organ function is followed by irreversible cell damage and death.
The major causes of shock are hypovolemic shock (often from acute hemorrhage), cardiogenic shock (for example from arrhythmia or heart failure), and vasodilatory shock (caused by vascular dilation, as seen for example in cerebral trauma, drug intoxication, heat exposure, or septic shock accompanying a gram negative bacterial infection). The symptoms and signs of shock are well known to the clinician, and include lethargy, confusion, cold extremities that are often moist and cyanotic, prolonged capillary filling time, a weak and rapid pulse, and (ultimately) profound hypotension.
Septic shock is a type of vasodilatory shock that is often accompanied by a clinical presentation that suggests infection, such as fever, chills, warm, flushed skin, and hemodynamic instability (characterized by a falling and rising blood pressure). Septic shock is an often fatal condition that accompanies severe microbial infections, frequently with gram-negative bacteria such as Escherichia coli, Pseudomonas aeruginosa and Klebsiella or Bacteroides species. Gram-positive bacterial infections can also lead to septic shock, particularly those infections caused by Staphylococcus aureus and the Pneumococcus. The bacterial infections can be acquired by routes such as ingestion, personal contact, or trauma, but infections are often nosocomial consequences of therapeutic procedures, including implantation of indwelling catheters or prosthetic devices. Septic shock often occurs in immunocompromised subjects, and therefore has been an increasing problem in recent years because of the increasing number of individuals who are immunocompromised. For example, subjects with HIV disease or who are taking immunosuppressive drugs for the treatment of cancer or organ transplantation rejection are at increased risk of developing septic shock.
In view of the above, there exists a need for agents that counteract aberrations in blood pressure, including hypotension and the vasodilation associated with shock.